From August 1933-August 1934, Anami served as regimental commander of the 2nd Guard Regiment of the Imperial Guards. He was subsequently Commandant of the Tokyo Military Preparatory School, and promoted to major general in March 1935.

From August 1936, Anami served as Chief of the Military Administration Bureau of the War Ministry. He became Chief of the Personnel Bureau in March 1937 and was promoted to lieutenant general in March the following year.

In May 1943, Anami was promoted to full general. As the war conditions in the Pacific deteriorated for the Japanese, the Second Area Army was reassigned to the Southern Theater from November 1943, where Anami directed operations in western New Guinea and Halmahera.

As War Minister, Anami was outspoken against the idea of surrender, despite his awareness that Japan's losses on the battlefield and the destruction of Japan's cities and industrial capability by American bombing meant that by this point that Japan had lost the war militarily.[3] Even after the bombings of Hiroshima and Nagasaki, Anami opposed acceptance of the Potsdam Declaration, and proposed instead that a large-scale battle be fought on the Japanese mainland causing such massive Allied casualties that Japan would somehow be able to evade surrender and perhaps even keep some of what it had conquered.[4]

Eventually, his arguments against what he perceived to be the dishonor of surrender were overcome when Emperor Hirohito directly requested an end to the war himself; Anami's supporters suggested that he either vote against surrender or resign from the Cabinet. Instead, he ordered his officers to concede, later saying to his brother-in-law, "As a Japanese soldier, I must obey my Emperor."[5] He informed the officers of the War Ministry of the decision, and that as it was an Imperial command, they must obey.[5] His refusal to support any action against the Imperial decision was a key point in the failure of the Kyūjō Incident, an attempted military coup d'état by junior officers to prevent the surrender announcement from being broadcast.[3]

On 14 August 1945, Anami signed the surrender document with the rest of the cabinet, then committed suicide by seppuku early the next morning.[6] His suicide note read: "I—with my death—humbly apologize to the Emperor for the great crime."[7] This "cryptic" note is open to multiple interpretations.[8]